Project Summary Population-based studies have traditionally focused on measurement of body fat (i.e. obesity) to assess the contribution of poor lifestyles to insulin resistance and cardiovascular risk. While much less recognized is the role of skeletal muscle in these conditions. Built on our proposed biobehavioral model which incorporates multi- dimensional evaluation of skeletal muscle health (i.e. mass, function, strength, and intermuscular fat infiltration) and its molecular transducer (i.e. myokine response to whole body vibration), the fundamental objective of this proposal is to evaluate the systemic contribution of skeletal muscle health in mediating the role of obesogenic lifestyles (i.e. psychosocial stress, unhealthy diet and physical inactivity) on insulin resistance and the development of preclinical markers of cardiovascular disease (CVD) (i.e. arterial stiffness, carotid intima media thickness and endothelial function). To evaluate the impact of environmental factors on manifestation of biological markers, genetic influences must be controlled. Building on our Georgia CV Twin Study which has evaluated a multi-ethnic twin samples of 532 twin pairs with roughly equal number of African Americans (AA) and European Americans (EA) 4 times over 15 years and has physical activity and psychosocial stress collected during these visits, we will conduct one additional follow-up visit (age range 22-45 yrs) to measure skeletal muscle health, insulin resistance and preclinical markers of CVD. The specific aims are to test the hypotheses that: (1) Obesogenic lifestyle factors (i.e. psychosocial stress, physical inactivity and unhealthy diet) will jointly or distinctively impair skeletal muscle health, and impaired skeletal muscle health will be the pathway through which obesogenic lifestyle factors exert their influence on insulin resistance and preclinical markers of CVD. (2) Myokine response to whole body vibration will be the molecular transducers mediating the effect of skeletal muscle health on insulin resistance and preclinical markers of CVD. (3) Ethnicity and gender may modify the influence of obesogenic lifestyle factors upon aim 1 and 2. The secondary aims are: (1) To examine whether skeletal muscle health can explain the health disparity between AAs and EAs in the risk of type 2 diabetes and CVD. (2) To examine the potential effects of gene-environment interactions on skeletal muscle response to obesogenic lifestyles. This proposal represents a paradigm shift by focusing on impairments in skeletal muscle rather than adiposity as a cause of poor lifestyle induced metabolic and vascular dysfunction. This information can not only guide the effective dissemination of the knowledge and increase the success rate of behavior changes, but also has the potential to generate new treatment strategies targeting the critical illness in which skeletal muscle as a determinant of survival. Furthermore, increased understanding of the mechanisms contributing to health disparities between AAs and EAs will enable the development of ethnicity- specific prevention strategies.